After a Trial, Silence

By ALEX BERENSON

Published: November 21, 2007

Prescriptions for the cholesterol-lowering drugs Zetia and Vytorin are written for almost 800,000 Americans every week, at a cost this year of about $4 billion. Yet it still is not clear how well the drugs work.

Nearly two years after the medicines' makers, Merck and Schering-Plough, completed a clinical trial of the drugs, they still have not released the findings. The delay has led to a growing chorus of complaints from cardiologists. And yesterday, the companies responded by promising to publish a portion of the results next March -- but not the entire set of data.

Doctors say that decision is highly unusual and will do little to quell concerns about the trial, as well as broader questions about the effectiveness of the drugs.

Cardiologists have been awaiting the results of the trial, called Enhance, to learn how well Zetia and Vytorin work. If they are not as effective as other cholesterol medicines, patients taking them may be putting themselves at unnecessary risk of heart attacks.

''There's clearly some rightful interest in what the results are,'' said Dr. Allen J. Taylor, chief of cardiology at Walter Reed Army Medical Center. ''You've got millions of people treated with the drugs.''

Whatever its results, the trial will not answer all questions about Zetia and Vytorin, either positively or negatively. Those answers may have to wait for a bigger study that will not be completed until at least 2010. But with so many patients taking the drugs, cardiologists are looking for whatever information they can get.

The delay in publishing the Enhance results also raises broad questions about whether the drug industry is sticking to its promises to improve the disclosure of clinical trials. After sharp criticism for failing to disclose trials that had negative results, drug makers promised two years ago to publicly register clinical trials in advance and promptly disclose their findings. But in practice they face few penalties for failing to meet those promises.

Of particular concern in this case is that Merck and Schering-Plough said yesterday that they had changed the trial's ''primary endpoint'' -- the main medical result being measured. The companies now say that they will use only partial results to assess the trial's success in deterring the formation of plaque that can cause artery blockages and lead to heart attacks.

Merck and Schering-Plough say that the change is appropriate and will enable them to finish their work in time to present the trial's results in March, at the American College of Cardiology annual conference in Chicago.

But scientists generally assume that for a clinical trial to be valid, its goals must be defined before it begins and never changed afterward. Otherwise, the people conducting the trial could change their goals to conform to the data the trial has actually produced.

''This sounds highly unusual to me,'' said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. ''You need to live with your primary endpoint.''

Another big drug maker, Pfizer, for example, was harshly criticized in 2001 for reporting that its painkiller Celebrex caused fewer ulcers than older drugs after six months of use. Pfizer's study had originally been designed -- but failed -- to show that Celebrex caused fewer ulcers after a full year of use.

Yesterday, Merck and Schering said they did not yet know the results of the trial. They said they were changing the endpoint only because they want to be able to analyze the data more quickly.

A panel of outside scientists recommended the change last Friday, said Lee Davies, a spokesman for Schering. Mr. Davies declined to disclose the members of the panel.

Dr. Howard Weintraub, the clinical director of the New York University center for the prevention of cardiovascular disease, said cardiologists were especially concerned about the trial's results because Zetia works differently from other cholesterol-lowering medicines like Lipitor or Merck's own Zocor.

Unlike the other medicines, called statins, Zetia has not yet been proven to prevent heart attacks. The Food and Drug Administration approved it in 2002 on the basis of trials that showed it could lower LDL, or so-called bad cholesterol, by 15 to 20 percent.

Zetia is the brand name for a cholesterol-lowering medicine called ezetimibe. It can be taken with any statin. Vytorin is a single pill that combines Zetia with simvastatin, the active ingredient in Merck's Zocor statin.

Together, Zetia and Vytorin have grabbed nearly 20 percent of the American market for cholesterol-lowering drugs, because of aggressive marketing from Merck and Schering-Plough that highlights Zetia's uniqueness among cholesterol medicines.

Because Zetia's cholesterol-lowering effect comes on top of that produced by statins, doctors often prescribe the drug in combination with low-dose statins, as an alternative to increasing the statin dose. Some patients do not like taking high-dose statins because they can cause muscle pain.